U.S. patent application number 11/298245 was filed with the patent office on 2006-07-13 for dibenzoxazepinone derivatives and uses thereof.
This patent application is currently assigned to Roche Palo Alto LLC. Invention is credited to Ralph New III Harris, James M. Kress, David Bruce Repke, Russell Stephen Stabler.
Application Number | 20060154914 11/298245 |
Document ID | / |
Family ID | 36384398 |
Filed Date | 2006-07-13 |
United States Patent
Application |
20060154914 |
Kind Code |
A1 |
Harris; Ralph New III ; et
al. |
July 13, 2006 |
Dibenzoxazepinone derivatives and uses thereof
Abstract
Compounds of the Formula I: ##STR1## wherein m, n, k, A, X, Y,
Z, Ar, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined
herein. The compounds are useful as 5-HT6 receptor antagonists.
Also provided are compositions comprising, methods of using, and
methods of making the subject compounds.
Inventors: |
Harris; Ralph New III;
(Redwood City, CA) ; Kress; James M.; (Sanford,
NC) ; Repke; David Bruce; (Milpitas, CA) ;
Stabler; Russell Stephen; (Boulder Creek, CA) |
Correspondence
Address: |
ROCHE PALO ALTO LLC;PATENT LAW DEPT. M/S A2-250
3431 HILLVIEW AVENUE
PALO ALTO
CA
94304
US
|
Assignee: |
Roche Palo Alto LLC
|
Family ID: |
36384398 |
Appl. No.: |
11/298245 |
Filed: |
December 9, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60634723 |
Dec 9, 2004 |
|
|
|
Current U.S.
Class: |
514/211.04 ;
514/211.11; 514/221; 540/488; 540/495; 540/547; 540/557 |
Current CPC
Class: |
C07D 413/04 20130101;
C07D 413/06 20130101; C07D 243/38 20130101; C07D 267/20 20130101;
C07D 281/16 20130101 |
Class at
Publication: |
514/211.04 ;
514/211.11; 514/221; 540/488; 540/495; 540/547; 540/557 |
International
Class: |
A61K 31/553 20060101
A61K031/553; A61K 31/551 20060101 A61K031/551 |
Claims
1. A compound of the formula I: ##STR83## wherein A is C(.dbd.O) or
CH.sub.2; X is --O--, --S(O).sub.q--, or --NR.sup.8--; Y is --N--
or --CH--; Z is --CR.sup.6R.sup.7).sub.r--, or --S(O).sub.t--; Ar
is optionally substituted aryl or optionally substituted
heteroaryl; each R.sup.1 is independently hydrogen or alkyl; each
of R.sup.2, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen
or alkyl; each of R.sup.3 and R.sup.4 is independently halo, alkyl,
haloalkyl, heteroalkyl, alkoxy, cyano, --S(O).sub.s--R.sup.c,
--C(.dbd.O)--NR.sup.cR.sup.d, --SO.sub.2--NR.sup.cR.sup.d,
--N(R.sup.c)--C(.dbd.O)--R.sup.d, or --C(.dbd.O)--R.sup.c; each of
R.sup.c and R.sup.d is independently hydrogen or alkyl; each of m
and n is independently an integer from 0 to 3; r is an integer from
1 to 3; and each of k, q, s, and t is independently an integer from
0 to 2.
2. The compound of formula I, wherein said compound of the formula
II: ##STR84## or a pharmaceutically acceptable salt, solvate or
prodrug thereof, wherein A is C(.dbd.O) or CH.sub.2; X is --O--,
--S(O).sub.q--, or --NR.sup.8--; Y is --N-- or --CH--; Z is
--CR.sup.6R.sup.7).sub.q--, or --S(O).sub.t--; each R.sup.1 is
independently hydrogen or alkyl; each of R.sup.2, R.sup.6, R.sup.7,
R.sup.8 is independently hydrogen or alkyl; each of R.sup.3,
R.sup.4, and R.sup.5 is independently halo, alkyl, haloalkyl,
heteroalkyl, alkoxy, cyano, --S(O).sub.s--R.sup.c,
--C(.dbd.O)--NR.sup.cR.sup.d, --SO.sub.2--NR.sup.cR.sup.d,
--N(R.sup.c)--C(.dbd.O)--R.sup.d, or --C(.dbd.O)--R.sup.c; each of
R.sup.c and R.sup.d is independently hydrogen or alkyl; each of m,
n, and p is independently an integer from 0 to 3; r is an integer
from 1 to 3; and each of k, q, s, and t is independently an integer
from 0 to 2.
3. The compound according to claim 1, wherein A is C.dbd.O.
4. The compound according to claim 1, wherein A is
--CH.sub.2--.
5. The compound according to claim 4, wherein Z is --S(O).sub.t--,
wherein t is as defined in claim 1.
6. The compound according to claim 1, wherein each of R.sup.3,
R.sup.4, and R.sup.5 is independently alkyl, alkoxy, halo,
hydroxyl, cyano, haloalkyl, or --S(O).sub.u-alkyl, and wherein u is
an integer from 0 to 2.
7. The compound according to claim 6 wherein m is 0 or 1.
8. The compound according to claim 7, wherein R.sup.3 is halo.
9. The compound according to claim 6, wherein n is 0 or 1.
10. The compound according to claim 9, wherein R.sup.4 is halo,
alkyl, or --S(O).sub.u-alkyl, wherein u is as defined in claim
3.
11. The compound according to claim 5, wherein p is 0 or 1.
12. The compound according to claim 10, wherein R.sup.5 is halo,
alkyl, alkoxy, haloalkyl, cyano, hydroxyl, or --S(O).sub.u-alkyl,
wherein u is as defined in claim 3.
13. The compound according to claim 1, wherein X is --S(O).sub.q--,
and wherein q is as defined in claim 1.
14. The compound according to claim 1, wherein X is --O--.
15. The compound according to claim 14, wherein Y is --CH--.
16. The compound according to claim 14, wherein Y is --N--.
17. The compound according to claim 16, wherein Z is
--CR.sup.6R.sup.7).sub.r-- or --S(O).sub.t--, wherein r, t,
R.sup.6, and R.sup.7 are as defined in claim 1.
18. The compound according to claim 17, wherein Z is
--(CR.sup.6R.sup.7).sub.t--, wherein r, R.sup.6, and R.sup.7 are as
defined in claim 1.
19. The compound according to claim 18, wherein R.sup.6 and R.sup.7
are hydrogen.
20. The compound according to claim 1, wherein k is 0.
21. The compound according to claim 1, wherein R.sup.2 is hydrogen
or alkyl.
22. The compound according to claim 2 1, wherein R.sup.2 is
hydrogen or methyl.
23. The compound according to claim 1, wherein said compound is
selected from the group consisting of:
10-Benzyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one;
10-(4-Fluoro-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-on-
e;
10-(3-Fluoro-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-
11-one; 10-(2-Fluoro-benzyl)-4-piperazin-1-yl-10H-dibenzo
[b,f][1,4]oxazepin-11-one;
4-Piperazin-1-yl-10-(3-trifluoromethyl-benzyl)-10H-dibenzo[b,f][1,4]oxaze-
pin-11-one;
3-(11-Oxo-4-piperazin-1-yl-11H-dibenzo[b,f][1,4]oxazepin-10-ylmethyl)-ben-
zonitrile;
10-(3-Chloro-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-on-
e;
10-Benzyl-2-chloro-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-o-
ne;
10-(3-Methyl-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-1-
1-one;
10-Phenethyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one-
;
10-(3-Methoxy-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-
-one;
10-(4-Methanesulfonyl-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4-
]oxazepin-11-one;
10-Benzyl-4-piperazin-1-yl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one;
10-Benzyl-8-tert-butyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-
-one;
10-Benzyl-7-fluoro-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-1-
1-one;
10-(3-Chloro-benzyl)-7-fluoro-4-piperazin-1-yl-10H-dibenzo[b,f][1,-
4]oxazepin-11-one;
7-Fluoro-10-phenethyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-o-
ne;
10-(3-Phenyl-propyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-1-
1-one;
10-Benzyl-8-ethanesulfonyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]o-
xazepin-11-one;
10-Benzyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]thiazepin-11-one;
10-Benzyl-8-fluoro-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one;
10-(5-Chloro-thiophen-2-ylmethyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]-
-oxazepin-11-one;
10-Benzyl-9-fluoro-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one;
10-Benzyl-6-fluoro-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one-
;
10-(3-Chloro-benzyl)-6-fluoro-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxa-
zepin-11-one;
6-Fluoro-10-phenethyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-o-
ne; 10-(3-Chloro-benzyl)-8-fluoro-4-piperazin-1-yl-10H-dibenzo
[b,f][1,4]oxazepin-11-one;
8-Fluoro-4-piperazin-1-yl-10-(3-trifluoromethyl-benzyl)-10H-dibenzo[b,f][-
1,4]oxazepin-11-one;
8-Fluoro-10-(4-fluoro-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxaze-
pin-11-one;
4-Piperazin-1-yl-10-pyridin-3-ylmethyl-10H-dibenzo[b,f][1,4]oxazepin-11-o-
ne;
10-(3-Hydroxy-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin--
11-one;
10-Benzenesulfonyl-4-(4-methyl-piperazin-1-yl)-10,11-dihydro-dibe-
nzo[b,f][1,4]-oxazepine;
8-Fluoro-10-(3-hydroxy-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxaz-
epin-11-one;
10-Benzyl-8-chloro-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one;
8-Chloro-10-(3-chloro-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxaz-
epin-11-one;
8-Chloro-4-piperazin-1-yl-10-(3-trifluoromethyl-benzyl)-10H-dibenzo[b,f][-
1,4]oxazepin-11-one;
10-(1H-Indol-3-ylmethyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-1-
1-one; and
10-Benzyl-2-methyl-4-piperidin-4-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one.
24. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 and a pharmaceutically
acceptable carrier.
25. A method for treating a central nervous system disease state in
a subject, said disease state selected from psychoses,
schizophrenia, manic depressions, neurological disorders, memory
disorders, attention deficit disorder, Parkinson's disease,
amyotrophic lateral sclerosis, Alzheimer's disease, food uptake
disorders, and Huntington's disease, said method comprising
administering to said subject a therapeutically effective amount of
a compound of claim 1.
26. A method for preparing a benzoxazepinone compound of the
formula: ##STR85## said method comprising reacting an amino
benzoxazepinone compound of the formula: ##STR86## with an amino
compound of the formula: ##STR87## to produce the benzoxazepinone
compound, wherein each of m and n is independently an integer from
0 to 3; Ar is optionally substituted aryl or optionally substituted
heteroaryl; A is C(.dbd.O) or CH.sub.2; X is --O--, --S(O).sub.q--,
or --NR.sup.8--; Z is --CR.sup.6R.sup.7).sub.r--, or
--S(O).sub.t--; each R.sup.1 is independently alkyl; each of
R.sup.6, R.sup.7, R.sup.8 is independently hydrogen or alkyl; each
of R.sup.3, R.sup.4, and R.sup.5 is independently halo, alkyl,
haloalkyl, heteroalkyl, alkoxy, cyano, --S(O).sub.s--R.sup.c,
--C(.dbd.O)--NR.sup.cR.sup.d, --SO.sub.2--NR.sup.cR.sup.d,
--N(R.sup.c)--C(.dbd.O)--R.sup.d, or --C(.dbd.O)--R.sup.c; each of
R.sup.c and R.sup.d is independently hydrogen or alkyl; each of m,
n, and p is independently an integer from 0 to 3; r is an integer
from 1 to 3; and each of k, q, s, and t is independently an integer
from 0 to 2. R.sup.2a is hydrogen, alkyl, or an amino-protecting
group; and each of X.sup.1 and X.sup.2 is independently a leaving
group.
Description
CROSS-REFERENCE
[0001] This application claims the benefit of priority of U.S.
Provisional Patent Application Ser. No. 60/634,723 filed Dec. 9,
2004, the disclosure of which is incorporated herein by reference
in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to dibenzoxazepinone compounds, and
associated compositions, methods for use as therapeutic agents, and
methods of preparation thereof.
BACKGROUND OF THE INVENTION
[0003] The actions of 5-hydroxytryptamine (5-HT) as a major
modulatory neurotransmitter in the brain are mediated through a
number of receptor families termed 5-HT1, 5-HT2, 5- HT3, 5-HT4,
5-HT5, 5-HT6, and 5-HT7. Based on a high level of 5-HT6 receptor
mRNA in the brain, it has been stated that the 5-HT6 receptor may
play a role in the pathology and treatment of central nerve system
disorders. In particular, 5-HT2-selective and 5-HT6 selective
ligands have been identified as potentially useful in the treatment
of certain CNS disorders such as Parkinson's disease, Huntington's
disease, anxiety, depression, manic depression, psychoses,
epilepsy, obsessive compulsive disorders, mood disorders, migraine,
Alzheimer's disease (enhancement of cognitive memory), sleep
disorders, feeding disorders such as anorexia, bulimia and obesity,
panic attacks, akathisia, attention deficit hyperactivity disorder
(ADHD), attention deficit disorder (ADD), withdrawal from drug
abuse such as cocaine, ethanol, nicotine and benzodiazepines,
schizophrenia, and also disorders associated with spinal trauma
and/or head injury such as hydrocephalus. Such compounds are also
expected to be of use in the treatment of certain gastrointestinal
(GI) disorders such as functional bowel disorder. See for example,
B. L. Roth et al., J. Pharmacol. Exp. Ther., 1994, 268, pages
1403-14120, D. R. Sibley et al., Mol. Pharmacol., 1993, 43,
320-327, A. J. Sleight et al., Neurotransmission, 1995, 11, 1-5,
and A. J. Sleight et al., Serotonin ID Research Alert, 1997, 2(3),
115-8.
[0004] While some 5-HT6 and 5-HT2A modulators have been disclosed,
there continues to be a need for compounds that are useful for
modulating the 5-HT6 receptor, the 5-HT2A receptor, or both.
SUMMARY
[0005] The present invention provides compounds of the Formula I:
##STR2## wherein [0006] A is C(.dbd.O) or CH.sub.2; [0007] X is
--O--, --S(O).sub.q--, or --NR.sup.8--; [0008] Y is --N-- or
--CH--; [0009] Z is --(CR.sup.6R.sup.7).sub.r--, or --S(O).sub.t--;
[0010] Ar is optionally substituted aryl or optionally substituted
heteroaryl each R.sup.1 is independently hydrogen or alkyl; [0011]
each of R.sup.2, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or alkyl; [0012] each of R.sup.3 and R.sup.4 is
independently halo, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano,
--S(O).sub.s--R.sup.c, --C(.dbd.O)--NR.sup.cR.sup.d,
--SO.sub.2--NR.sup.cR.sup.d, --N(R.sup.c)--C(.dbd.O)--R.sup.d, or
--C(.dbd.O)--R.sup.c; [0013] each of R.sup.c and R.sup.d is
independently hydrogen or alkyl; [0014] each of m and n is
independently an integer from 0 to 3; [0015] r is an integer from 1
to 3; and [0016] each of k, q, s, and t is independently an integer
from 0 to 2.
[0017] It should be understood that the scope of the present
invention encompasses not only the various isomers that may exist
but also the various mixture of isomers that may be formed.
Furthermore, the scope of the present invention also encompasses
solvates and salts of compounds of formula II. ##STR3## or a
pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein [0018] A is C(.dbd.O) or CH.sub.2; [0019] X is --O--,
--S(O).sub.q--, or --NR.sup.8--; [0020] Y is --N-- or --CH--;
[0021] Z is --(CR.sup.6R.sup.7).sub.r--, or --S(O).sub.t--; [0022]
each R.sup.1 is independently hydrogen or alkyl; [0023] each of
R.sup.2, R.sup.6, R.sup.7, R.sup.8 is independently hydrogen or
alkyl; [0024] each of R.sup.3, R.sup.4, and R.sup.5 is
independently halo, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano,
--S(O).sub.s--R.sup.c, --C(.dbd.O)--NR.sup.cR.sup.d,
--SO.sub.2--NR.sup.cR.sup.d, --N(R.sup.c)--C(.dbd.O)--R.sup.d, or
--C(.dbd.O)R.sup.c; [0025] each of R.sup.c and R.sup.d is
independently hydrogen or alkyl; [0026] each of m, n, and p is
independently an integer from 0 to 3; [0027] r is an integer from 1
to 3; and [0028] each of k, q, s, and t is independently an integer
from 0 to 2.
[0029] The present invention also provides methods for preparing
the aforementioned compounds. The subject methods may comprise, in
certain embodiments, reacting an amino benzoxazepinone compound of
the formula: ##STR4## with an amino compound of the formula:
##STR5## to yield a benzoxazepinone compound of the formula:
##STR6## wherein Ar, R.sup.1, R.sup.3, R.sup.4, A, X, Y, Z, k, m
and n are those defined herein; R.sup.2a is hydrogen, alkyl, or an
amino-protecting group; and each of X.sup.1and X.sup.2 is
independently a leaving group.
[0030] In another embodiment, methods may comprise reacting a
heterocyclyl benzoxazepinone compound of the formula: ##STR7## with
an aryl compound of the formula: ##STR8## to produce a
benzoxazepinone compound of the formula: ##STR9## wherein X.sup.3
is a leaving group; and Ar, R.sup.1, R.sup.2, R.sup.3, R.sup.4, A,
X, Y, Z, k, m, and n are those defined herein.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The invention provides substituted benzoxazepinone
compounds, associated compositions, methods for use as therapeutic
agents, and methods of preparation thereof. One embodiment of the
present invention provides heterocyclyl-substituted (e.g.,
piperazinyl-substituted) benzoxazepinone compounds and associated
pharmaceutical compositions, and methods for using the same in the
treatment of central nervous system (CNS) diseases and
gastrointestinal tract disorders.
[0032] All publications cited in this disclosure are incorporated
herein by reference in their entirety.
Definitions
[0033] Unless otherwise stated, the following terms used in this
Application, including the specification and claims, have the
definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms "a",
"an," and "the" include plural referents unless the context clearly
dictates otherwise.
[0034] "Agonist" refers to a compound that enhances the activity of
another compound or receptor site.
[0035] "Alkyl" means the monovalent linear or branched saturated
hydrocarbon moiety, consisting solely of carbon and hydrogen atoms,
having from one to twelve carbon atoms. "Lower alkyl" refers to an
alkyl group of one to six carbon atoms (i.e.,
"C.sub.1-C.sub.6alkyl"). Examples of alkyl groups include, but are
not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the
like.
[0036] "Alkoxy" means a moiety of the formula --OR, wherein R is an
alkyl moiety as defined herein. Examples of alkoxy moieties
include, but are not limited to, methoxy, ethoxy, isopropoxy, and
the like.
[0037] "Antagonist" refers to a compound that diminishes or
prevents the action of another compound or receptor site.
[0038] "Aryl" means a monovalent cyclic aromatic hydrocarbon moiety
consisting of a mono-, bi- or tricyclic aromatic ring. The aryl
group can be optionally substituted as defined herein. Examples of
aryl moieties include, but are not limited to, phenyl, naphthyl,
naphthalenyl, phenanthryl, fluorenyl, indenyl, pentalenyl,
azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl,
diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl,
benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl,
benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl,
benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl,
ethylenedioxyphenyl, and the like, including partially hydrogenated
derivatives thereof.
[0039] "Cycloalkyl" means a saturated carbocyclic moiety consisting
of mono- or bicyclic rings; Cycloalkyl can optionally be
substituted with one or more substituents, wherein each substituent
is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino,
monoalkylamino, or dialkylamino, unless otherwise specifically
indicated. Examples of cycloalkyl moieties include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and the like, including partially unsaturated
derivatives thereof such as cyclohexenyl, cyclopentenyl, and the
like.
[0040] "Cycloalkylalkyl" means a moiety of the formula --R'--R'',
where R' is alkylene and R'' is cycloalkyl as defined herein.
[0041] "Heteroalkyl" means an alkyl radical as defined herein
wherein one, two or three hydrogen atoms have been replaced with a
substituent independently selected from the group consisting of
--OR.sup.a, --NR.sup.bR.sup.c, and --S(O).sub.nR.sup.d (where n is
an integer from 0 to 2), with the understanding that the point of
attachment of the heteroalkyl radical is through a carbon atom,
wherein R.sup.a is hydrogen, acyl, alkyl, cycloalkyl, or
cycloalkylalkyl; R.sup.b and R.sup.c are independently of each
other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and
when n is 0, R.sup.d is hydrogen, alkyl, cycloalkyl, or
cycloalkylalkyl, and when n is 1 or 2, R.sup.d is alkyl,
cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or
dialkylamino. Representative examples include, but are not limited
to, 2-hydroxyethyl, 3-hydroxypropyl,
2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,
1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,
2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,
2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,
aminosulfonylpropyl, methylaminosulfonylmethyl,
methylaminosulfonylethyl, methylaminosulfonylpropyl, and the
like.
[0042] "Heteroaryl" means a monocyclic or bicyclic monovalent
radical of 5 to 12 ring atoms having at least one aromatic ring
containing one, two, or three ring heteroatoms selected from N, O,
or S, the remaining ring atoms being C, with the understanding that
the attachment point of the heteroaryl radical will be on an
aromatic ring. The heteroaryl ring may be optionally substituted as
defined herein. Examples of heteroaryl moieties include, but are
not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl,
benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyridinyl,
pyridazyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,
isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,
benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,
benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,
triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,
naphihyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl,
acridinyl and the like, including partially hydrogenated
derivatives thereof.
[0043] The terms "halo" and "halogen", which may be used
interchangeably, refer to a substituent fluoro, chloro, bromo, or
iodo.
[0044] "Haloalkyl" means alkyl as defined herein in which one or
more hydrogen has been replaced with same or different halogen.
Exemplary haloalkyls include --CH.sub.2Cl, --CH.sub.2CF.sub.3,
--CH.sub.2CCl.sub.3, perfluoroalkyl (e.g., --CF.sub.3), and the
like.
[0045] "Optionally substituted", when used in association with
"aryl", or "heteroaryl" means an aryl, or heteroaryl that is
optionally substituted independently with one or more, e.g., one to
four substituents, preferably one or two substituents, selected
from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl,
halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino,
mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl,
--COR (where R is hydrogen, alkyl, phenyl or phenylalkyl),
--CR'R'').sub.n--COOR (where n is an integer from 0 to 5, R' and
R'' are independently hydrogen or alkyl, and R is hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl),
--(CR'R'').sub.n--CONR.sup.aR.sup.b (where n is an integer from 0
to 5, R' and R'' are independently hydrogen or alkyl, and R.sup.a
and R.sup.b are, independently of each other, hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl),
--S(O).sub.s--R.sup.c (where s is 0, 1 or 2; and R.sup.c is
hydrogen or alkyl), --SO.sub.2--NR.sup.cR.sup.d (where each of
R.sup.c and R.sup.d is independently hydrogen or alkyl), and
--N(R.sup.c)--C(.dbd.O)--R.sup.d (where each of R.sup.c and R.sup.d
is independently hydrogen or alkyl).
[0046] "Leaving group" means the group with the meaning
conventionally associated with it in synthetic organic chemistry,
i.e., an atom or group displaceable under substitution reaction
conditions. Examples of leaving groups include, but are not limited
to, halogen, alkane- or arylenesulfonyloxy, such as
methanesulfonyloxy, ethanesulfonyloxy, thiomethyl,
benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy,
optionally substituted benzyloxy, isopropyloxy, acyloxy, and the
like.
[0047] "Modulator" means a molecule that interacts with a target.
The interactions include, but are not limited to, agonist,
antagonist, and the like, as defined herein.
[0048] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not.
[0049] "Disease state" means any disease, condition, symptom, or
indication.
[0050] "Inert organic solvent" or "inert solvent" means the solvent
is inert under the conditions of the reaction being described in
conjunction therewith, including for example, benzene, toluene,
acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform,
methylene chloride or dichloromethane, dichloroethane, diethyl
ether, ethyl acetate, acetone, methyl ethyl ketone, methanol,
ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine,
and the like. Unless specified to the contrary, the solvents used
in the reactions of the present invention are inert solvents.
[0051] "Pharmaceutically acceptable" means useful in preparing a
pharmaceutical composition that is generally safe, non-toxic, and
neither biologically nor otherwise undesirable and includes that
which is acceptable for veterinary as well as human pharmaceutical
use.
[0052] "Pharmaceutically acceptable salts" of a compound means
salts that are pharmaceutically acceptable, as defined herein, and
that possess the desired pharmacological activity of the parent
compound. Such salts include:
[0053] acid addition salts formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like;
[0054] or formed with organic acids such as acetic acid,
benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid,
ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic
acid, glutamic acid, glycolic acid, hydroxynaphtoic acid,
2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,
malonic acid, mandelic acid, methanesulfonic acid, muconic acid,
2-naphthalenesulfonic acid, propionic acid, salicylic acid,
succinic acid, tartaric acid, p-toluenesulfonic acid,
trimethylacetic acid, and the like; or
[0055] salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic or inorganic base. Acceptable organic bases include
diethanolamine, ethanolamine, N-methylglucamine, triethanolamine,
tromethamine, and the like. Acceptable inorganic bases include
aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium
carbonate and sodium hydroxide.
[0056] The preferred pharmaceutically acceptable salts are the
salts formed from acetic acid, hydrochloric acid, sulfuric acid,
methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid,
citric acid, sodium, potassium, calcium, zinc, and magnesium.
[0057] It should be understood that all references to
pharmaceutically acceptable salts include solvent addition forms
(solvates) or crystal forms (polymorphs) as defined herein, of the
same acid addition salt.
[0058] The terms "pro-drug" and "prodrug", which may be used
interchangeably herein, refer to any compound which releases an
active parent drug according to formula I in vivo when such prodrug
is administered to a mammalian subject. Prodrugs of a compound of
formula I are prepared by modifying one or more functional group(s)
present in the compound of formula I in such a way that the
modification(s) may be cleaved in vivo to release the parent
compound. Prodrugs include compounds of formula I wherein a
hydroxy, amino, or sulfhydryl group in a compound of Formula I is
bonded to any group that may be cleaved in vivo to regenerate the
free hydroxyl, amino, or sulfhydryl group, respectively. Examples
of prodrugs include, but are not limited to, esters (e.g., acetate,
formate, and benzoate derivatives), carbamates (e.g.,
N,N-dimethylaminocarbonyl) of hydroxy functional groups in
compounds of formula I, N-acyl derivatives (e.g. N-acetyl)
N-Mannich bases, Schiff bases and enaminones of amino functional
groups, oximes, acetals, ketals and enol esters of ketone and
aldehyde functional groups in compounds of Formula I, and the like,
see Bundegaard, H. "Design of Prodrugs" p1-92, Elesevier, New
York-Oxford (1985), and the like.
[0059] "Protective group" or "protecting group" means the group
which selectively blocks one reactive site in a multifunctional
compound such that a chemical reaction can be carried out
selectively at another unprotected reactive site in the meaning
conventionally associated with it in synthetic chemistry. Certain
processes of this invention rely upon the protective groups to
block reactive nitrogen and/or oxygen atoms present in the
reactants. For example, the terms "amino-protecting group" and
"nitrogen protecting group" are used interchangeably herein and
refer to those organic groups intended to protect the nitrogen atom
against undesirable reactions during synthetic procedures.
Exemplary nitrogen protecting groups include, but are not limited
to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl
(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like.
The artisan in the art will know how to choose a group for the ease
of removal and for the ability to withstand the following
reactions.
[0060] "Solvates" means solvent addition forms that contain either
stoichiometric or non stoichiometric amounts of solvent. Some
compounds have a tendency to trap a fixed molar ratio of solvent
molecules in the crystalline solid state, thus forming a solvate.
If the solvent is water the solvate formed is a hydrate, when the
solvent is alcohol, the solvate formed is an alcoholate. Hydrates
are formed by the combination of one or more molecules of water
with one of the substances in which the water retains its molecular
state as H.sub.2O, such combination being able to form one or more
hydrate.
[0061] "Subject" means mammals and non-mammals. Mammals means any
member of the mammalia class including, but not limited to, humans;
non-human primates such as chimpanzees and other apes and monkey
species; farm animals such as cattle, horses, sheep, goats, and
swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice, and guinea pigs; and
the like. Examples of non-mammals include, but are not limited to,
birds, and the like. The term "subject" does not denote a
particular age or sex.
[0062] "Therapeutically effective amount" means an amount of a
compound that, when administered to a subject for treating a
disease state, is sufficient to effect such treatment for the
disease state. The "therapeutically effective amount" will vary
depending on the compound, disease state being treated, the
severity or the disease treated, the age and relative health of the
subject, the route and form of administration, the judgement of the
attending medical or veterinary practitioner, and other
factors.
[0063] The terms "those defined above" and "those defined herein"
when referring to a variable incorporates by reference the broad
definition of the variable as well as preferred, more preferred and
most preferred definitions, if any.
[0064] "Treating" or "treatment" of a disease state includes:
[0065] (i) preventing the disease state, i.e. causing the clinical
symptoms of the disease state not to develop in a subject that may
be exposed to or predisposed to the disease state, but does not yet
experience or display symptoms of the disease state. [0066] (ii)
inhibiting the disease state, i.e., arresting the development of
the disease state or its clinical symptoms, or [0067] (iii)
relieving the disease state , i.e., causing temporary or permanent
regression of the disease state or its clinical symptoms.
[0068] The terms "treating", "contacting" and "reacting" when
referring to a chemical reaction means adding or mixing two or more
reagents under appropriate conditions to produce the indicated
and/or the desired product. It should be appreciated that the
reaction which produces the indicated and/or the desired product
may not necessarily result directly from the combination of two
reagents which were initially added, i.e., there may be one or more
intermediates which are produced in the mixture which ultimately
leads to the formation of the indicated and/or the desired
product.
Nomenclature
[0069] In general, the nomenclature used in this Application is
based on AUTONOM.TM. v.4.0, a Beilstein Institute computerized
system for the generation of IUPAC systematic nomenclature. For
convenience, the IUPAC numbering of the positions of representative
quinoline compounds described herein is shown by the formula:
[0070] Chemical structures shown herein were prepared using
ISIS.TM./Draw version 2.5. Any open valency appearing on a carbon,
oxygen or nitrogen atom in the structures herein indicates the
presence of a hydrogen.
Compounds of the Invention
[0071] One aspect of the present invention provides compounds of
the formula I: ##STR10## wherein [0072] A is C(.dbd.O) or CH.sub.2;
[0073] X is --O--, --S(O).sub.q--, or --NR.sup.8--; [0074] Y is
--N-- or --CH--; [0075] Z is --(CR.sup.6R.sup.7)-- or
--S(O).sub.t--; [0076] Ar is optionally substituted aryl or
optionally substituted heteroaryl each R.sup.1 is independently
hydrogen or alkyl; [0077] each of R.sup.2, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or alkyl; [0078] each of R.sup.3
and R.sup.4 is independently halo, alkyl, haloalkyl, heteroalkyl,
alkoxy, cyano, --S(O).sub.s--R.sup.c, --C(.dbd.O)--NR.sup.cR.sup.d,
--SO.sub.2NR.sup.cR.sup.d, --N(R.sup.c)--C(.dbd.O)--R.sup.d, or
--C(.dbd.O)--R.sup.c; [0079] each of R.sup.c and R.sup.d is
independently hydrogen or alkyl; [0080] each of m and n is
independently an integer from 0 to 3; [0081] r is an integer from 1
to 3; and [0082] each of k, q, s, and t is independently an integer
from 0 to 2.
[0083] It should be understood that the scope of the present
invention encompasses not only the various isomers that may exist
but also the various mixture of isomers that may be formed.
Furthermore, the scope of the present invention also encompasses
prodrugs, solvates and salts of compounds of formula I.
[0084] In some embodiments, A is C.dbd.O.
[0085] In other embodiments, A is --CH.sub.2--. In these particular
embodiments, preferably Z is --S(O).sub.t--, where t is as defined
herein.
[0086] Yet in other embodiments, each of R.sup.3 and R.sup.4 is
independently alkyl, alkoxy, halo, hydroxyl, cyano, haloalkyl, or
--S(O).sub.u-alkyl, and wherein u is an integer from 0 to 2.
[0087] In some embodiments, R.sup.3 is halo.
[0088] Still in other embodiments, R.sup.4 is halo, alkyl, or
--S(O).sub.u-alkyl, where u is as defined herein.
[0089] In certain embodiments Ar is optionally substituted aryl. In
such embodiments, Ar is more preferably optionally substituted
phenyl.
[0090] In some embodiments Ar is optionally substituted heteroaryl.
Preferred heteroaryl include thienyl, pyridyl and indolyl, each of
which may be optionally substituted. Exemplary heteroaryl include
pyridin-3-yl, 2-chlorothien-5-yl and indol-3-yl.
[0091] In other embodiments, m is 0 or 1.
[0092] Yet still in other embodiments, n is 0 or 1.
[0093] Still in other embodiments, p is 0 or 1.
[0094] Yet in other embodiments, X is --S(O).sub.q-where q is as
defined herein.
[0095] In many embodiments, X is --O--.
[0096] In some embodiments, Y is --CH--.
[0097] In other embodiments, Y is --N--.
[0098] In certain embodiments, Z is --CR.sup.6R.sup.7).sub.r- or
--S(O).sub.t--, where r, t, R.sup.6, and R.sup.7 are as defined
herein. In one particular embodiment, Z is
--(CR.sup.6R.sup.7).sub.r-- where r, R.sup.6, and R.sup.7 are as
defined herein. Within this particular embodiment, preferably
R.sup.6 and R.sup.7 are hydrogen.
[0099] Yet in other embodiments, k is 0.
[0100] In other embodiments, R.sup.2 is hydrogen or alkyl. In
specific embodiments, R.sup.2 is hydrogen or methyl.
[0101] The compounds of the invention in many embodiments are more
specifically of the formula II: ##STR11## wherein [0102] A is
C(.dbd.O) or CH.sub.2; [0103] X is --O--, --S(O).sub.q--, or
--NR.sup.8--; [0104] Y is --N-- or --CH--; [0105] Z is
--(CR.sup.6R.sup.7).sub.r--, or --S(O).sub.t--; [0106] each R.sup.1
is independently hydrogen or alkyl; [0107] each of R.sup.2,
R.sup.6, R.sup.7, R.sup.8 is independently hydrogen or alkyl;
[0108] each of R.sup.3, R.sup.4, and R.sup.5 is independently halo,
alkyl, haloalkyl, heteroalkyl, alkoxy, cyano,
--S(O).sub.s--R.sup.c, --C(.dbd.O)--NR.sup.cR.sup.d,
--SO.sub.2--NR.sup.cR.sup.d, --N(R.sup.c)--C(.dbd.O)--R.sup.d, or
--C(.dbd.O)--R.sup.c; [0109] each of R.sup.c and R.sup.d is
independently hydrogen or alkyl; [0110] each of m, n, and p is
independently an integer from 0 to 3; [0111] r is an integer from 1
to 3; and [0112] each of k, q, s, and t is independently an integer
from 0 to 2.
[0113] It should be understood that the scope of the present
invention encompasses not only the various isomers which may exist
but also the various mixture of isomers which may be formed.
Furthermore, the scope of the present invention also encompasses
prodrugs, solvates and salts of compounds of formula II.
[0114] In some embodiments, A is C.dbd.O.
[0115] In other embodiments, A is --CH.sub.2--. In this particular
embodiment, preferably Z is --S(O).sub.t--, where t is as defined
herein.
[0116] Yet in other embodiments, each of R.sup.3, R.sup.4, and
R.sup.5 is independently alkyl, alkoxy, halo, hydroxyl, cyano,
haloalkyl, or --S(O).sub.u-alkyl, and wherein u is an integer from
0 to 2.
[0117] In some embodiments, R.sup.3 is halo.
[0118] Still in other embodiments, R.sup.4 is halo, alkyl, or
--S(O).sub.u-alkyl, where u is as defined herein.
[0119] Yet in other embodiments, R.sup.5 is halo, alkyl, alkoxy,
haloalkyl, cyano, hydroxyl, or --S(O).sub.u-alkyl, where u is as
defined herein.
[0120] In other embodiments, m is 0 or 1.
[0121] Yet still in other embodiments, n is 0 or 1.
[0122] Still in other embodiments, p is 0 or 1.
[0123] Yet in other embodiments, X is --S(O).sub.q-where q is as
defined herein.
[0124] In many embodiments, X is --O--.
[0125] In some embodiments, Y is --CH--.
[0126] In other embodiments, Y is --N--.
[0127] In certain embodiments, Z is --CR.sup.6R.sup.7).sub.r-- or
--S(O).sub.t-, where r, t, R.sup.6, and R.sup.7 are as defined
herein. In one particular embodiment, Z is
--CR.sup.6R.sup.7).sub.r--, where r, R.sup.6, and R.sup.7 are as
defined herein. Within this particular embodiment, preferably
R.sup.6 and R.sup.7 are hydrogen.
[0128] Yet in other embodiments, k is 0.
[0129] In other embodiments, R.sup.2 is hydrogen or alkyl. In
specific embodiments, R.sup.2 is hydrogen or methyl.
[0130] It should be appreciated that combinations of the different
groups described herein may form other embodiments. In this manner,
a variety of different compounds are embodied within the present
invention.
[0131] Where any of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.c and R.sup.d herein are alkyl or
contain an alkyl moiety, such alkyl is preferably lower alkyl, i.e.
C.sub.1-C.sub.6alkyl, and more preferably C.sub.1-C.sub.4alkyl.
[0132] Representative compounds in accordance with the invention
are shown in Table 1 together with melting point or mass spectrum
M+H, and the experimental examples (described below) associated
with each compound. TABLE-US-00001 TABLE 1 MP (.degree. C.) or #
Structure Name M + H+HZ,1/52 1 ##STR12##
10-Benzyl-4-piperazin-1-yl-10H- dibenzo[b,f][1,4]oxazepin-11-one
198-199.degree. C. (HCl salt) 2 ##STR13##
10-(4-Fluoro-benzyl)-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 214-216.degree. C. (HCl salt) 3
##STR14## 10-(3-Fluoro-benzyl)-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 191-192.degree. C. (HCl salt) 4
##STR15## 10-(2-Fluoro-bvenzyl)-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 404 (M + 1) 5 ##STR16##
4-Piperzazin-1-yl-10-(3-trifluoromethyl-
benzyl)-10H-dibenzo[b,f][1,4]oxazepin-11- one 454 (M + 1) 6
##STR17## 3-(11-Oxo-4-piperazin-1-yl-11H-
dibenzo[b,f][1,4]oxazepin-10-ylmethyl)- benzonitrile
192-194.degree. C. (HCl salt) 7 ##STR18##
10-(3-Chloro-benzyl)-4-piperazin-1-yl-
10H-dibenzo[b,f][1,4]oxazepin-11-one 420, 422 (M + 1) 8 ##STR19##
10-Benzyl-2-chloro-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 196-197.degree. C. (HCl salt) 9
##STR20## 10-(3-Methyl-benzyl)-4-piperazin-1-yl-
10H-dibenzo[b,f][1,4]oxazepin-11-one 400 (M + 1) 10 ##STR21##
10-Phnethyl-4-piperazin-1-yl-10H- dibenzo[b,f][1,4]oxazepin-11-one,
hydrochloride 400 (M + 1) 11 ##STR22##
10-(3-Methoxy-benzyl)-4-piperzazin-1-yl-
10H-dibenzo[b,f][1,4]oxazepin-11-one 416 (M + 1) 12 ##STR23##
10-(4-Methanesulfonyl-benzyl)-4- piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxaezpin-11-one 464 (M + 1) 13 ##STR24##
10-Benzyl-4-piperazin-1-yl-5,10-dihydro-
dibenzo[b,e][1,4]diazepin-11-one 322-323.degree. C. (HCl salt) 14
##STR25## 10-Benzyl-8-tert-butyl-4-piperazin-1-yl-
10H-dibenzo[b,f][1,4]oxazepin-11-one 292-293.degree. C. (HCl salt)
15 ##STR26## 10-Benzyl-7-fluoro-4-piperazin-1-yl-10H-
dibvenzo[b,f][1,4]oxazepin-11-one 404 (M + 1) 16 ##STR27##
10-(3-Chloro-benzyl)-7-fluoro-4-piperazin-
1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one 483 (M + 1) 17 ##STR28##
7-Fluoro-10-phenethyl-4-piperazin-1-yl-
10H-dibenzo[b,f][1,4]oxazepin-11-one, hydrochloride 418 (M + 1) 18
##STR29## 10-(3-Phenyl-propyl)-4-piperazin-1-yl-
10H-dibenzo[b,f][1,4]oxazepin-11-one, hydrochloride 415 (M + 1) 19
##STR30## 10-Benzyl-8-ethanesulfonyl-4-piperazin-1-
yl-10H-dibenzo[b,f][1,4]oxazepin-11-one 184-185.degree. C. (HCl
salt) 20 ##STR31## 10-Benzyl-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]thiazepin-11-one 301-302.degree. C. (HCl salt) 21
##STR32## 10-Benzyl-8-fluoro-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 404 (M + 1) 22 ##STR33##
10-(5-Chloro-thiophen-2-ylmethyl)-4-
piperazin-1-yl-10H-dibenzo[b,f][1,4]- oxazepin-11-one,
hydrochloride 427 (M + 1) 23 ##STR34##
10-Benzyl-9-fluoro-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 178-180.degree. C. (HCl salt) 24
##STR35## 10-Benzyl-6-fluoro-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 404 (M + 1) 25 ##STR36##
10-(3-Chloro-benzyl)-6-fluoro-4-piperazin-
1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one 438, 440 (M + 1) 26
##STR37## 6-Fluoro-10-phenethyl-4-piperazin-1-yl-
10H-dibenzo[b,f][1,4]oxazepin-11-one, hydrochloride 418 (M + 1) 27
##STR38## 10-(3-Chloro-benzyl)-8-fluoro-4-piperazin-
1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one 438, 440 (M + 1) 28
##STR39## 8-Fluoro-4-piperazin-1-yl-10-(3-
trifluoromethyl-benzyl)-10H- dibenzo[b,f][1,4]oxazepin-11-one 472
(M + 1) 29 ##STR40## 8-Fluoreo-10-(4-fluoro-benzyl)-4-piperazin-
1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one 422 (M + 1) 30 ##STR41##
4-Piperazin-1-yl-10-pyridin-3-ylmethyl-
10H-dibenzo[b,f][1,4]oxazepin-11-one 387 (M + 1) 31 ##STR42##
10-(3-Hydroxy-benzyl)-4-piperazin-1-yl-
10H-dibenzo]b,f][1,4]oxazepin-11-one 402 (M + 1) 32 ##STR43##
10-Benzenesulfonyl-4-(4-methyl-piperazin-
1-yl)-10,11-dihydro-dibenzo[b,f][1,4]- oxazepin 242-243.degree. C.
33 ##STR44## 8-Fluoro-10-(3-hydroxy-benzyl)-4- piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 420 (M + 1) 34 ##STR45##
10-Benzyl-8-chloro-4-piperazin-1-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-one 420, 422 (M + 1) 35 ##STR46##
8-Chloro-10-(3-chloro-benzyl)-4-piperazin-
1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one 454, 456 (M + 1) 36
##STR47## 8-Chloro-4-piperazin-1-yl-10-(3-
trifluoromethyl-benzyl)-10H- dibenzo[b,f][1,4]oxazepin-11-one 488,
490 (M + 1) 37 ##STR48## 10-(1H-Indol-3-ylmethyl)-4-piperazin-1-yl-
10H-dibenzo[b,f][1,4]oxazepin-11-one 426 (M + 1) 38 ##STR49##
10-Benzyl-2-methyl-4-piperidin-4-yl-10H-
dibenzo[b,f][1,4]oxazepin-11-,one, hydrochloride 400 (M + 1)
[0133] Another aspect of the invention provides a composition
comprising a therapeutically effective amount of at least one
compound of Formula I and a pharmaceutically acceptable
carrier.
[0134] Yet another aspect of the invention provides a method for
treating a central nervous system (CNS) disease state in a subject
comprising administering to the subject a therapeutically effective
amount of a compound of Formula I. The disease state may comprise,
for example, psychoses, schizophrenia, manic depressions,
neurological disorders, memory disorders, attention deficit
disorder, Parkinson's disease, amyotrophic lateral sclerosis,
Alzheimer's disease or Huntington's disease.
[0135] Still another aspect of the present invention provides a
method for treating a disorder of the gastrointestinal tract in a
subject comprising administering to the subject a therapeutically
effective amount of a compound of Formula I.
[0136] Another aspect of the present invention provides a method
for producing a compound of Formula I.
Synthesis
[0137] Compounds of the present invention can be made by a variety
of methods depicted in the illustrative synthetic reaction schemes
shown and described below.
[0138] The starting materials and reagents used in preparing these
compounds generally are either available from commercial suppliers,
such as Aldrich Chemical Co., or are prepared by methods known to
those skilled in the art following procedures set forth in
references such as Fieser and Fieser's Reagents for Organic
Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's
Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989,
Volumes 1-5 and Supplementals; and Organic Reactions, Wiley &
Sons: New York, 2004, Volumes 1-56. The following synthetic
reaction schemes are merely illustrative of some methods by which
the compounds of the present invention can be synthesized, and
various modifications to these synthetic reaction schemes can be
made and will be suggested to one skilled in the art having
referred to the disclosure contained in this Application.
[0139] The starting materials and the intermediates of the
synthetic reaction schemes can be isolated and purified if desired
using conventional techniques, including but not limited to,
filtration, distillation, crystallization, chromatography, and the
like. Such materials can be characterized using conventional means,
including physical constants and spectral data.
[0140] Unless specified to the contrary, the reactions described
herein preferably are conducted under an inert atmosphere at
atmospheric pressure at a reaction temperature range of from about
-78.degree. C. to about 150.degree. C., more preferably from about
0.degree. C. to about 125.degree. C., and most preferably and
conveniently at about room (or ambient) temperature, e.g., about
20.degree. C.
[0141] Scheme A below illustrates some of the synthetic procedures
usable to prepare compounds of the invention. Numerous synthetic
routes to benzoxazepinone are known and may be used in preparation
of the subject compounds, and the procedure of Scheme A is only
exemplary. Specific examples of the procedures of Scheme A are
provided in the following Experimental section. ##STR50##
[0142] In Scheme A, a nitro-aryl compound A-1 is coupled with an
aniline compound A-2 to provide a compound A-3. Typically, this
coupling reaction is conducted under an inert aprotic solvent, such
as methylene chloride, toluene or a mixture thereof. The
substituent A.sup.1 of the nitro-aryl compound A-1 is typically a
carbonyl-containing group such as carboxylic acid, ester or an acyl
halide. Alternatively, the substituent A.sup.1 of the nitro-aryl
compound A-1 may be a methylene-containing group with a leaving
group that is capable of being displaced by the amino group of the
aniline compound A-2.
[0143] Intramolecular cyclization of the compound A-3 then provides
dibenzoxazepinone compound A-4 (where A is C.dbd.O). The
intramolecular cyclization is generally conducted by heating the
compound A-3 in the presence of a base, such as sodium hydroxide,
and a polar solvent. Often the intramolecular cyclization reaction
may be conducted in water.
[0144] The nitro group in compound A-4 is then reduced to an amino
group to provide an aniline compound A-5. Suitable reaction
conditions for reducing a nitro group to an amino group are well
known to one skilled in the art. Typically, the reduction of the
nitro group is achieved by hydrogenation reaction in the presence
of a palladium catalyst and an acid, such as hydrochloric acid.
When the substituent A is a carbonyl group (C.dbd.O), under certain
reaction conditions one can simultaneously reduce the carbonyl
group to a methylene group, if so desired.
[0145] Aniline compound A-5 is reacted with compound is treated
with amino compound A-6 in a cyclization reaction that produces
piperazinyl compound A-7. Alkylation of compound A-8 with compound
A-8 then affords compound A-9. When R.sup.2a is an amino protecting
group, it can be removed to provide a compound of Formula I where R
is hydrogen.
[0146] Alternatively, compound A-4 can be treated directly with
compound A-8 to affect an N-alkylation and provide compound A-b 10.
The nitro group in compound A-10 may then be reduced to an amino
group to provide the corresponding aniline compound A-11. Compound
A-11 may then be treated with compound A-6 to afford compound
A-9.
[0147] Numerous variations on the procedure of Scheme A are
possible and will be apparent to those skilled in the art having
the disclosure of the present invention. More specific details for
producing compounds of Formula I are described in the Examples
section below.
Utility
[0148] The compounds of the invention have selective affinity for
5-HT receptors, including the 5-HT.sub.6 the 5-HT.sub.2A receptor,
or both, and as such are expected to be useful in the treatment of
certain CNS disorders such as Parkinson's disease, Huntington's
disease, anxiety, depression, manic depression, psychosis,
epilepsy, obsessive compulsive disorders, mood disorders, migraine,
Alzheimer's disease (enhancement of cognitive memory), sleep
disorders, feeding disorders such as anorexia, bulimia, and
obesity, panic attacks, akathisia, attention deficit hyperactivity
disorder (ADHD), attention deficit disorder (ADD), withdrawal from
drug abuse such as cocaine, ethanol, nicotine and benzodiazepines,
schizophrenia, and also disorders associated with spinal trauma
and/or head injury such as hydrocephalus. Such compounds are also
expected to be of use in the treatment of certain GI
(gastrointestinal) disorders such functional bowel disorder and
irritable bowel syndrome.
Testing
[0149] The pharmacology of the compounds of this invention was
determined by art recognized procedures. The in vitro techniques
for determining the affinities of test compounds at the 5-HT6
receptor and the 5-HT2A receptor in radioligand binding and
functional assays are described below.
Administration and Pharmaceutical Composition
[0150] The present invention includes pharmaceutical compositions
comprising at least one compound of the present invention, or an
individual isomer, racemic or non-racemic mixture of isomers or a
pharmaceutically acceptable salt or solvate thereof, together with
at least one pharmaceutically acceptable carrier, and optionally
other therapeutic and/or prophylactic ingredients.
[0151] In general, the compounds of the present invention will be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. Suitable dosage ranges are typically 1-500 mg daily,
preferably 1-100 mg daily, and most preferably 1-30 mg daily,
depending upon numerous factors such as the severity of the disease
to be treated, the age and relative health of the subject, the
potency of the compound used, the route and form of administration,
the indication towards which the administration is directed, and
the preferences and experience of the medical practitioner
involved. One of ordinary skill in the art of treating such
diseases will be able, without undue experimentation and in
reliance upon personal knowledge and the disclosure of this
Application, to ascertain a therapeutically effective amount of the
compounds of the present invention for a given disease.
[0152] In general, compounds of the present invention will be
administered as pharmaceutical formulations including those
suitable for oral (including buccal and sub-lingual), rectal,
nasal, topical, pulmonary, vaginal, or parenteral (including
intramuscular, intraarterial, intrathecal, subcutaneous and
intravenous) administration or in a form suitable for
administration by inhalation or insufflation. The preferred manner
of administration is generally oral using a convenient daily dosage
regimen which can be adjusted according to the degree of
affliction.
[0153] A compound or compounds of the present invention, together
with one or more conventional adjuvants, carriers, or diluents, may
be placed into the form of pharmaceutical compositions and unit
dosages. The pharmaceutical compositions and unit dosage forms may
be comprised of conventional ingredients in conventional
proportions, with or without additional active compounds or
principles, and the unit dosage forms may contain any suitable
effective amount of the active ingredient commensurate with the
intended daily dosage range to be employed. The pharmaceutical
compositions may be employed as solids, such as tablets or filled
capsules, semisolids, powders, sustained release formulations, or
liquids such as solutions, suspensions, emulsions, elixirs, or
filled capsules for oral use; or in the form of suppositories for
rectal or vaginal administration; or in the form of sterile
injectable solutions for parenteral use. Formulations containing
about one (1) milligram of active ingredient or, more broadly,
about 0.01 to about one hundred (100) milligrams, per tablet, are
accordingly suitable representative unit dosage forms.
[0154] The compounds of the present invention may be formulated in
a wide variety of oral administration dosage forms. The
pharmaceutical compositions and dosage forms may comprise a
compound or compounds of the present invention or pharmaceutically
acceptable salts thereof as the active component. The
pharmaceutically acceptable carriers may be either solid or liquid.
Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories, and dispersible granules. A solid carrier
may be one or more substances which may also act as diluents,
flavoring agents, solubilizers, lubricants, suspending agents,
binders, preservatives, tablet disintegrating agents, or an
encapsulating material. In powders, the carrier generally is a
finely divided solid which is a mixture with the finely divided
active component. In tablets, the active component generally is
mixed with the carrier having the necessary binding capacity in
suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from about one (1) to
about seventy (70) percent of the active compound. Suitable
carriers include but are not limited to magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,
gelatine, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as carrier,
providing a capsule in which the active component, with or without
carriers, is surrounded by a carrier, which is in association with
it. Similarly, cachets and lozenges are included. Tablets, powders,
capsules, pills, cachets, and lozenges may be as solid forms
suitable for oral administration.
[0155] Other forms suitable for oral administration include liquid
form preparations including emulsions, syrups, elixirs, aqueous
solutions, aqueous suspensions, or solid form preparations which
are intended to be converted shortly before use to liquid form
preparations. Emulsions may be prepared in solutions, for example,
in aqueous propylene glycol solutions or may contain emulsifying
agents, for example, such as lecithin, sorbitan monooleate, or
acacia. Aqueous solutions can be prepared by dissolving the active
component in water and adding suitable colorants, flavors,
stabilizers, and thickening agents. Aqueous suspensions can be
prepared by dispersing the finely divided active component in water
with viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other well
known suspending agents. Solid form preparations include solutions,
suspensions, and emulsions, and may contain, in addition to the
active component, colorants, flavors, stabilizers, buffers,
artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like.
[0156] The compounds of the present invention may be formulated for
parenteral administration (e.g., by injection, for example bolus
injection or continuous infusion) and may be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions
may take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, for example solutions in aqueous polyethylene
glycol. Examples of oily or nonaqueous carriers, diluents, solvents
or vehicles include propylene glycol, polyethylene glycol,
vegetable oils (e.g., olive oil), and injectable organic esters
(e.g., ethyl oleate), and may contain formulatory agents such as
preserving, wetting, emulsifying or suspending, stabilizing and/or
dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilization from solution for constitution before use with a
suitable vehicle, e.g., sterile, pyrogen-free water.
[0157] The compounds of the present invention may be formulated for
topical administration to the epidermis as ointments, creams or
lotions, or as a transdermal patch. Ointments and creams may, for
example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
containing one or more emulsifying agents, stabilizing agents,
dispersing agents, suspending agents, thickening agents, or
coloring agents. Formulations suitable for topical administration
in the mouth include lozenges comprising active agents in a
flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatine
and glycerine or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0158] The compounds of the present invention may be formulated for
administration as suppositories. A low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter is first melted
and the active component is dispersed homogeneously, for example,
by stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and to solidify.
[0159] The compounds of the present invention may be formulated for
vaginal administration. Pessaries, tampons, creams, gels, pastes,
foams or sprays containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0160] The compounds of the present invention may be formulated for
nasal administration. The solutions or suspensions are applied
directly to the nasal cavity by conventional means, for example,
with a dropper, pipette or spray. The formulations may be provided
in a single or multidose form. In the latter case of a dropper or
pipette, this may be achieved by the patient administering an
appropriate, predetermined volume of the solution or suspension. In
the case of a spray, this may be achieved for example by means of a
metering atomizing spray pump.
[0161] The compounds of the present invention may be formulated for
aerosol administration, particularly to the respiratory tract and
including intranasal administration. The compound will generally
have a small particle size for example of the order of five (5)
microns or less. Such a particle size may be obtained by means
known in the art, for example by micronization. The active
ingredient is provided in a pressurized pack with a suitable
propellant such as a chlorofluorocarbon (CFC), for example,
dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
The aerosol may conveniently also contain a surfactant such as
lecithin. The dose of drug may be controlled by a metered valve.
Alternatively the active ingredients may be provided in a form of a
dry powder, for example a powder mix of the compound in a suitable
powder base such as lactose, starch, starch derivatives such as
hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The
powder carrier will form a gel in the nasal cavity. The powder
composition may be presented in unit dose form for example in
capsules or cartridges of e.g., gelatine or blister packs from
which the powder may be administered by means of an inhaler.
[0162] When desired, formulations can be prepared with enteric
coatings adapted for sustained or controlled release administration
of the active ingredient. For example, the compounds of the present
invention can be formulated in transdermal or subcutaneous drug
delivery devices. These delivery systems are advantageous when
sustained release of the compound is necessary and when patient
compliance with a treatment regimen is crucial. Compounds in
transdermal delivery systems are frequently attached to an
skin-adhesive solid support. The compound of interest can also be
combined with a penetration enhancer, e.g., Azone
(1-dodecylazacycloheptan-2-one). Sustained release delivery systems
are inserted subcutaneously into the subdermal layer by surgery or
injection. The subdermal implants encapsulate the compound in a
lipid soluble membrane, e.g., silicone rubber, or a biodegradable
polymer, e.g., polylactic acid.
[0163] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0164] Other suitable pharmaceutical carriers and their
formulations are described in Remington: The Science and Practice
of pharmacy 1995, edited by E. W. Martin, Mack Publishing Company,
19th edition, Easton, Pa. Representative pharmaceutical
formulations containing a compound of the present invention are
described in the Examples below.
EXAMPLES
[0165] The following preparations and examples are given to enable
those skilled in the art to more clearly understand and to practice
the present invention. They should not be considered as limiting
the scope of the invention, but merely as being illustrative and
representative thereof. Additional compounds prepared using the
experimental procedures below are shown in Table 1.
Example 1
[0166] This example illustrates a process for producing
2-chloro-N-(2-hydroxyphenyl)-3-nitro-benzamide. ##STR51##
[0167] To a suspension of 7.8 g (38.7 mmole) of
2-chloro-3-nitrobenzoic acid in 100 mL of methylene chloride was
added 5 drops of DMF and 4.35 mL (50 mmole) of oxalyl chloride. The
reaction mixture was stirred at 22.degree. C. for 2 hours. The
solution was then concentrated under reduced pressure. The residue
was dissolved in 75 mL of toluene, and this solution was added
dropwise to a stirred mixture of 4.4 g (40 mmole) of 2-aminophenol
and 11 g (.1 mole) of sodium carbonate in 50 mL of water and 50 mL
of toluene. The reaction mixture was stirred at 22.degree. C. for
16 hours. The reaction mixture was diluted with 50 mL of water and
the precipitated solid was collected, washed with water and dried
in vacuo to provide 9.75 g (86% yield) of the title compound. M.p.
158-159.degree. C.
Example 2
[0168] This example illustrates a process for producing
4-nitro-10H-dibenzo[b,f][1,4]oxazepin-11-one. ##STR52##
[0169] A mixture of 5 g (17.1 mmole) of
2-chloro-N-(2-hydroxyphenyl)-3-nitro-benzamide and 0.8 g (20 mmole)
of sodium hydroxide in 100 mL of water was heated under reflux for
2.5 hours. The mixture was chilled in an ice bath for 0.5 hour and
the precipitated solid was collected, washed with water and dried
in vacuo to give 4.03 g (91% yield) of the title compound. M.p.
298-301.degree. C.
Example 3
[0170] This example illustrates a process for producing
4-amino-10H-dibenzo [b,f][1,4]oxazepin-11-one hydrochloride.
##STR53##
[0171] A mixture of 5 g of
4-nitro-10H-dibenzo[b,f][1,4]oxazepin-11-one, 1 g of 10% palladium
on carbon, and 3.25 mL (19.5 mmole) of 6 N hydrochloric acid in 400
mL of methanol was shaken under 45 psi hydrogen pressure at
22.degree. C. for 3 hours. The catalyst was removed by filtration
and washed with 1 L of methanol. The filtrate and washings were
combined and concentrated under reduced pressure. The residue was
triturated with 50 mL of ethanol. To this solution was slowly added
50 mL of ethyl ether and the crystalline product was collected and
dried in vacuo to give the title compound (5.1 g, 99% yield). M.p.
266-268.degree. C.
Example 4
[0172] This example illustrates a process for producing
10-benzyl-4-nitro-10H-dibenzo[b,f][1,4]oxazepin-11-one.
##STR54##
[0173] To a mixture of 0.64 g (2.5 mmole) of
4-nitro-10H-dibenzo[b,f][1,4]oxazepin-11-one and 1 g of powdered
potassium carbonate in 7 mL of DMF was added 0.3 mL (2.5 mmole) of
benzyl bromide. The reaction mixture was stirred at 22.degree. C.
for 16 hours. The solvent was removed under reduced pressure and
the residue was partitioned between 10 mL of water and 50 mL of
ethyl acetate. The organic phase was dried (magnesium sulfate) and
concentrated under reduced pressure. The residue was subjected to
low-pressure column chromatography over 100 g silica gel (230-400
mesh) eluting with 15% ethyl acetate in hexane. Product fractions
were combined and concentrated under reduced pressure to provide
the title compound as a heavy syrup (0.88 g, 88% yield).
M+H=347.
Example 5
[0174] This example illustrates a process for producing
4-amino-10-benzyl-10H-dibenzo[b,f][1,4]oxazepin-11-one
hydrochloride. ##STR55##
[0175] A mixture of 0.8 g (2.31 mmole) of
10-benzyl-4-nitro-10H-dibenzo[b,f][1,4]oxazepin-11-one and 0.3 g of
10% palladium on carbon in 35 mL of methanol was hydrogenated at 50
psi at 22.degree. C. for 3 hours. The catalyst was removed by
filtration and the filtrate was reduced to about 5 mL under reduced
pressure. The pH of the solution was adjusted to about pH 2 by
addition of 1.0 M hydrogen chloride in ethyl ether. The mixture was
concentrated under reduced pressure and the residue was
recrystallized from methanol/ethyl acetate/ethyl ether to provide
the title compound (0.407 g, 50% yield). M.p. 221-222.degree.
C.
Example 6
[0176] This example illustrates a process for producing
4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one,
hydrochloride. ##STR56##
[0177] A mixture of 3.6 g (20 mmole) of bis-(2-chloroethyl)amine
hydrochloride and 5 g of 4-amino-10H-dibenzo
[b,f][1,4]oxazepin-11-one hydrochloride was immersed in a
pre-heated 260.degree. C. oil bath. The reaction mixture was heated
at 260-270.degree. C. for 13 minutes. The dark residue was
dissolved in 200 mL of hot methanol and the volume was reduced to
about 50 mL by distillation. The light brown crystalline solid was
collected and dried in vacuo to give 5.5 g (87% yield) of the title
compound. M.p. 326-327.degree. C., M+H=296.
Example 7
[0178] This example illustrates a process for producing
10-benzyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one.
##STR57##
[0179] A solution of 0.3 g (0.95 mmole) of
4-amino-10-benzyl-10H-dibenzo[b,f][1,4]oxazepin-11-one,
hydrochloride and 0.17 g (0.95 mmole) of bis-(2-chloroethyl)amine,
hydrochloride in 2 mL of methanol was prepared. The solvent was
removed under reduced pressure. The residue was heated at
250.degree. C. for 1 minute. The glassy residue was subjected to
low-pressure column chromatography over silica gel (230-400 mesh)
eluting with 3% methanol in chloroform containing 0.25% of conc.
ammonium hydroxide. Product fractions were combined and
concentrated under reduced pressure and the residue was
recrystallized from ethyl ether/hexane to provide the title
compound (0.14 g, 38% yield). M.p. 198-199.degree. C. M+H=386.
Example 8
[0180] This example illustrates a process for producing
4-(4-benzylpiperazin-1-yl)-10H-dibenzo[b,f][1,4]oxazepin-11-one.
##STR58##
[0181] A mixture of 0.062 g (0.24 mmole) of
4-amino-10H-dibenzo[b,f][1,4]oxazepin-11-one, hydrochloride and
0.062 g (0.23 mmole) of benzyl-bis-(2-chloroethyl)-amine
hydrochloride was heated at 240.degree. C. for 1 minute. The dark,
glassy residue was subjected to low-pressure column chromatography
over silica gel (230-400 mesh) eluting with 1% methanol in
chloroform. Product fractions were combined and concentrated under
reduced pressure to give the title compound as a crystalline solid
(0.030 g, 32% yield). M.p. 201-202.degree. C.
Example 9
[0182] This example illustrates a process for producing
tert-butyl-[4-(11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4-yl)-piper-
azine-1-]-carboxylate. ##STR59##
[0183] To a stirred mixture of 0.87 g (2.62 mmole) of
4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one,
hydrochloride and 0.59 g (2.7 mmole) of di-tert-butyl dicarbonate
in 50 mL of THF was added 2 mL of pyridine, 5 mg of
4-dimethylaminopyridine and 0.5 mL of triethylamine (i.e., TEA).
The reaction mixture was stirred at 22.degree. C. for 1 hour. The
mixture was concentrated under reduced pressure and the residue was
partitioned between 50 mL of ethyl acetate and 20 mL of water. The
organic phase was washed with 10 mL of saturated sodium chloride,
dried (magnesium sulfate) and concentrated under reduced pressure.
The residue was recrystallized from ethyl ether to provide the
title compound (0.902 g, 87% yield). M.p. 231-232.degree. C.
M+H=396.
Example 10
[0184] This example illustrates a process for producing
4-[10-(4-fluoro-benzyl)-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4--
yl]-piperazine-1-carboxylic acid, tert-butyl ester. ##STR60##
[0185] A mixture of 0.05 g (0.126 mmole) of
tert-butyl-[4-(11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4-yl)-piper-
azine-l-]-carboxylate, 0.050 g (0.4 mmole) of powdered potassium
carbonate and 0.1 mL (0.8 mmole) of 4-fluorobenzyl bromide in 1.5
mL of DMF was stirred under a nitrogen atmosphere at 22.degree. C.
for 16 hours. The mixture was diluted with 10 mL of water and
extracted with 30 mL of ethyl ether. The organic phase was washed
with 2.times.10 mL water, dried (magnesium sulfate) and
concentrated under reduced pressure. A homogenous syrup remained
(0.06 g, 94% yield). M+H=504.
Example 11
[0186] This example illustrates a process for producing
4-[10-(3-fluoro-benzyl)-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4--
yl]-piperazine-1-carboxylic acid, tert-butyl ester.
[0187] Using the procedure of Example 10, 4-[10-(3-fluoro-benzyl)-1
1-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4-yl]-piperazine-1-carboxyl-
ic acid, tert-butyl ester was prepared from the appropriate
starting materials.
Example 12
[0188] This example illustrate a process for producing
10-(4-fluoro-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-on-
e, dihydrochloride. ##STR61##
[0189] A solution of 0.06 g (0.12 mmole) of
4-[10-(4-fluoro-benzyl)-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4--
yl]-piperazine-1-carboxylic acid, tert-butyl ester in 2 mL of
ethanol containing 2 mL of 6 N hydrochloric acid was heated under
reflux for 0.25 hour. The solution was concentrated under reduced
pressure and the residue was recrystallized from ethanol/ethyl
acetate/ether to provide the title compound (0.0465 g, 81% yield).
M.p. 214-216.degree. C.
Examples 13-15
[0190] Using the procedure of Example 12, the following compounds
were also prepared from the appropriate starting materials.
[0191]
10-(3-fluoro-benzyl)-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepi-
n-11-one, dihydrochloride. M.p. 191-192.degree. C., M+H=404;
[0192] 10-(2-fluoro-benzyl)-4-piperazin-1-yl-10H-dibenzo
[b,f][1,4]oxazepin-11-one, dihydrochloride; and
[0193]
4-piperazin-1-yl-10-(3-trifluoromethyl-benzyl)-10H-dibenzo[b,f][1,-
4]oxazepin-11-one, dihydrochloride.
Example 16
[0194] This example illustrates a process for producing
4-amino-5,10-dihydro-dibenzo[b,f][1,4]diazepin-11-one,
hydrochloride. ##STR62##
[0195] A mixture of 0.227 g (0.9 mmole) of
4-nitro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one [prepared
according to Breslin, et al, J. Med. Chem., 1995, 38,771] and 0.5
mL of 6 N hydrochloric acid in 30 mL of ethanol was hydrogenated
over 0.05 g of 10% palladium on carbon at 22.degree. C. and 50 psi
for 3 hours. The catalyst was removed by filtration and the
filtrate was concentrated under reduced pressure. The residue was
triturated with 1 mL of ethanol and 3 mL of ethyl acetate. The
light green crystalline solid was collected and dried in vacuo to
provide the title compound (0.229 g, 97% yield). M.p.
270-272.degree. C. (dec.). M+H=226.
Example 17
[0196] This example illustrates a process for producing
4-piperazin-1-yl-5,10-dihydro-dibenzo [b,e][1,4]diazepin-11-one,
dihydrochloride. ##STR63##
[0197] A mixture of 0.05 g (0.9 mmole) of
4-amino-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one,
hydrochloride and 0.036 g (0.2 mmole) of bis-(2-chloroethyl)amine,
hydrochloride was heated at 260.degree. C. in a sealed tube for 4
minutes. The residue was recrystallized from methanol to provide
the title compound as a light tan solid (0.029 g, 46% yield). M.p.
360.degree. C. (dec.). M+H=295.
Example 18
[0198] This example illustrates a process for producing
4-(11-Oxo-10,11-dihydro-5H-dibenzo[b,f][1,4]diazepin-4-yl)-piperazine-1-c-
arboxylic acid tert-butyl ester. ##STR64##
[0199] To a suspension of 0.25 grams (0.76 mmole)
4-piperazin-1-yl-5,10-dihydro-dibenzo[b,f][1,4]diazepin-11-one
dihydrochloride in 10 mL tetrahydrofuran was added 0.175 gram (0.8
mmole) di-tert-butyl dicarbonate and 0.3 mL (2.0 mmole)
triethylamine. The reaction mixture was stirred at 230 for 5 hours.
The solvent was removed under reduced pressure and the residue was
partitioned between 50 mL chloroform and 15 mL 10% sodium
bicarbonate. The organic phase was dried (magnesium sulfate) and
concentrated under reduced pressure. The residue was recrystallized
from ether/hexane to provide the title compound, 0.23 gram (77%),
m.p. 264-265.degree., M+H=395.
Example 19
[0200] This example illustrates a process for producing
4-(10-Benzyl-11-oxo-10,11-dihydro-5H-dibenzo[b,f][1,4]diazepin-4-yl)piper-
azine-1-carboxylic acid tert-butyl ester. ##STR65##
[0201] A mixture of 0.211 grams (0.535 mmole)
4-(11-oxo-10,11-dihydro-5H-dibenzo[b,f][1,4]diazepin-4-yl)-piperazine-1-c-
arboxylic acid tert-butyl ester, 0.6 mL 1.0M potassium
tert-butoxide in THF, and 0.064 mL (0.54 mmole) benzyl bromide in
3.0 mL DMF was stirred at 230 for 2 hours. The reaction mixture was
diluted with 10 mL water and extracted with 35 mL ethyl acetate.
The organic phase was dried (magnesium sulfate) and concentrated
under reduced pressure. The residue was subjected to low pressure
column chromatography over silica gel 230-400 mesh eluting with 15%
ethyl acetate in hexane. Product fractions were combined and
concentrated under reduced pressure to leave the title compound as
a white solid, 0.08 grams, m.p. 109-1100, M+H=485.
Example 20
[0202] This example illustrates a process for producing
10-Benzyl-4-piperazin-1-yl-5,10-dihydro-dibenzo[b,f][1,4]diazepin-11-one
dihydrochloride. ##STR66##
[0203] To a solution of 0.06 gram (0.123 mmole)
4-(10-benzyl-11-oxo-10,11-dihydro-5H-dibenzo[b,f][1,4]diazepin-4-yl)piper-
azine-1-carboxylic acid tert-butyl ester in 5.0 mL ethanol was
added 1.0 mL 6N hydrochloric acid. The reaction mixture was heated
under reflux for 3 minutes, then the solution was concentrated
under reduced pressure and the residue was recrystallized from
ethanol/ether to provide the title compound, 0.061 gram, m.p.
322-323.degree. (dec), M+H=385.
Example 21
[0204] This example illustrates a process for producing
2-Bromo-N-(2-mercapto-phenyl)-3-nitro-benzamide. ##STR67##
[0205] To a solution of 3.0 grams (12.2 mmole)
2-bromo-3-nitro-benzoic acid in 50 mL dichloromethane was added 1.6
mL (18 mmole) oxalyl chloride and 4 drops DMF. The reaction mixture
was stirred at 230 for 2 hours. The solution was concentrated under
reduced pressure and the residue was dissolved in 40 mL toluene.
This solution was added dropwise to a stirred mixture of 1.4 mL (13
mmole) 2-amino-benzenethiol and 1.7 grams sodium bicarbonate (20
mmole) in 35 mL toluene and 35 mL water at 0.degree.. The reaction
mixture was stirred at 0.degree. for 3 hours. The solid that
precipitated at the interface was collected, washed with water,
then hexane and dried to provide the title compound, 3.52 grams,
(82%) m.p. 152-1530.
Example 22
[0206] This example illustrates a process for producing
4-nitro-10H-dibenzo [b,f][1,4]thiazepin-11-one. ##STR68##
[0207] To a solution of 3.52 grams (10 mmole)
2-bromo-N-(2-mercapto-phenyl)-3-nitro-benzamide in 100 mL
acetonitrile was added 2.0 Ml (11 mmole) diisopropylethyl amine.
The reaction mixture was heated under reflux for 16 hours. The
solution was concentrated under reduced pressure. To the residue
was added 10 mL ethyl acetate and 10 mL water. The mixture was
stirred at 230 for 0.5 hour. The resulting light yellow solid was
collected, washed with water, ethyl acetate and hexane and dried to
provide the title compound, 2.12 grams, (78%), m.p. 259-2610.
Example 23
[0208] This example illustrates a process for producing
10-Benzyl-4-nitro-10H-dibenzo[b,f][1,4]thiazepin-11-one.
##STR69##
[0209] A mixture of 1.0 gram (3.7 mmole)
4-nitro-10H-dibenzo[b,f][1,4]thiazepin-11-one, 0.828 gram (6 mmole)
potassium carbonate and 0.45 mL (3.75 mmole) benzyl bromide in 10
mL DMF was stirred at 230 for 4 hours. The solution was
concentrated under reduced pressure and the residue was partitioned
between 200 mL ethyl acetate and 50 mL water. The organic phase was
dried (magnesium sulfate) and concentrated under reduced pressure.
The residue was recrystallized from ethyl ether to provide the
title compound, 0.796 gram, (58%) m.p. 223-224.degree..
Example 24
[0210] This example illustrate a process for producing
4-Amino-10-benzyl-10H-dibenzo[b,f][1,4]thiazepin-11-one
hydrochloride. ##STR70##
[0211] A mixture of 0.225 gram (0.62 mmole)
10-benzyl-4-nitro-10H-dibenzo[b,f][1,4]thiazepin-1 1-one, 0.06 gram
10% palladium on carbon and 0.5 mL 6N hydrochloric acid in 10 mL
ethanol was hydrogenated under 50 psi hydrogen gas at 230 for 2
hours. The mixture was filtered and concentrated under reduced
pressure. The residue was recrystallized from methanol/ether to
provide the title compound, 0.129 gram, m.p. 219-2200, M+H=333.
Example 25
[0212] This example illustrates a process for producing
10-Benzyl-4-piperazin-1-yl-10H-dibenzo[b,f][1,4]thiazepin-11-one
dihydrochloride monohydrate. ##STR71##
[0213] An intimate mixture of 0.1 gram (0.27 mmole)
4-amino-10-benzyl-10H-dibenzo[b,f][1,4]thiazepin-11-one
hydrochloride and 0.073 gram (0.41 mmole) bis-2-(chloroethyl) amine
hydrochloride was immersed in a preheated 2600 oil bath. The
reaction mixture was heated at 2600 for 3 minutes. The dark glassy
residue was subjected to low pressure column chromatography over
silica gel 230-400 mesh eluting with 5% methanol in chloroform
containing 0.25 % concentrated ammonium hydroxide. Product
fractions were combined and concentrated under reduced pressure.
The residue was converted to the hydrochloride salt and
recrystallized from methanol/ethyl acetate/ether to provide the
title compound, 0.074 grams, (65%), m.p. 301-3020 M+H=402.
Example 26
[0214] This example illustrates a process for producing
3-Bromo-2-iodo-5-methyl benzoic acid. ##STR72##
[0215] Twenty grams (0.87 mole) 2-amino-3-bromo-5-methyl benzoic
acid was suspended in 120 mL water with mechanical stirring. The
mixture was cooled in an ice bath and 100 mL concentrated sulfuric
acid was added slowly. A solution of 12 grams (0.141 mole) sodium
nitrite in 100 mL water was added dropwise over 0.5 hour. The
reaction mixture was stirred for an additional 0.25 hour at
0-5.degree.. The mixture was poured into a well-stirred solution of
24 grams (0.145 mole) potassium iodide in 100 mL water. The
resulting solid was collected by filtration and stirred in 200 mL
ethyl acetate. A solution of 200 mL 20% sodium hydrogen sulfite was
added slowly. The organic layer was separated, washed with 100 mL
20% sodium hydrogen sulfite, 50 mL saturated sodium chloride, dried
(magnesium sulfate) and concentrated under reduced pressure. The
residue was recrystallized from ether/hexane to provide the title
compound, 15 grams, m.p. 152-153.degree..
Example 27
[0216] This example illustrates a process for producing
3-Bromo-N-(2-hydroxy-phenyl)-2-iodo-5-methyl-benzamide.
##STR73##
[0217] To a solution of 5.0 grams (14.7 mmole)
3-bromo-2-iodo-5-methyl benzoic acid in 150 mL dichloromethane was
added 5 drops DMF and 3.0 mL (34.5 mmole) oxalyl chloride. The
reaction mixture was stirred at 230 for 2 hours. The solution was
concentrated under reduced pressure. The residue was dissolved in
100 mL toluene and 50 mL 10% sodium bicarbonate and 1.6 grams (14.7
mmole) 2-aminophenol were added. The mixture was stirred at 230 for
16 hours. The precipitate was collected, washed with water,
toluene, hexane, and dried to provide the title compound, 6 grams
(95%), m.p. 225-2260.
Example 28
[0218] This example illustrates a process for producing
4-Bromo-2-methyl-10H-dibenzo[b,f][1,4]oxazepin-11-one.
##STR74##
[0219] To a solution of 6.45 grams (14.9 mmole)
3-bromo-N-(2-hydroxy-phenyl)-2-iodo-5-methyl-benzamide in 25 mL THF
was added 15 mL 1.0 M potassium tert-butoxide in THF. The solution
was concentrated under reduced pressure and the residue was
dissolved in 15 mL DMF. The reaction mixture was heated under
reflux for 20 hours. The mixture was diluted with 100 mL water.
Ethyl acetate was added (200 mL) and the mixture was filtered. The
organic phase was extracted with 50 mL 5% sodium hydroxide, then it
was washed with 25 mL saturated sodium chloride, dried (magnesium
sulfate) and concentrated under reduced pressure. The residue was
subjected to low pressure column chromatography over silica gel
230-400 mesh eluting with 15% ethyl acetate in hexane. Product
fractions were combined and concentrated under reduced pressure.
The residue was recrystallized from ether/hexane to provide the
title compound, 1.36 grams (30%), m.p. 223-2240.
Example 29
[0220] This example illustrates a process for producing
10-Benzyl-4-bromo-2-methyl-10H-dibenzo [b,f][1,4] oxazepin-11-one.
##STR75##
[0221] To a solution of 0.5 gram (1.64 mmole)
4-bromo-2-methyl-10H-dibenzo[b,f][1,4]oxazepin-11-one in 5 mL DMF
was added 0.1 gram (2.5 mmole) 100% sodium hydride. After 5
minutes, 0.2 mL (1.7 mmole) benzyl bromide was added. The reaction
mixture was stirred at 23.degree. for 2 hours. The solution was
concentrated under reduced pressure and the residue was partitioned
between 20 mL water and 50 mL ethyl acetate. The organic phase was
dried (magnesium sulfate) and concentrated under reduced pressure.
The residue was subjected to low pressure column chromatography
over silica gel 230-400 mesh eluting with 5% ethyl acetate/hexane.
Product fractions were combined and concentrated under reduced
pressure to provide the title compound as a heavy oil, 0.46 gram
(71%), M+H=394.
Example 30
[0222] This example illustrates a process for producing
4-(10-Benzyl-2-methyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4-yl-
)-3,6-dihydro-2H-pyridine-1-carboxylic benzyl ester. ##STR76##
[0223] A mixture of 0.43 gram (1.09 mmole)
10-benzyl-4-bromo-2-methyl-10H-dibenzo[b,f][1,4]oxazepin-11-one,
0.374 gram (1.09 mmole)
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine--
1-carboxylic acid benzyl ester (P. R. Eastwood, Tetrahedron Letters
41: 3705-3708 (2000)), 0.451 gram (3.27 mmole) potassium carbonate,
and 0.054 gram (0.065 mmole)
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
complex with dichloromethane (1:1) in 5 mL DMF was heated at 800
for 3 hours. The mixture was concentrated under reduced pressure.
To the residue was added 50 mL ethyl acetate and 10 mL chloroform.
The mixture was filtered and concentrated under reduced pressure.
The residue was partitioned between 100 mL ethyl acetate and 20 mL
saturated sodium chloride. The organic phase was dried and
concentrated under reduced pressure. The residue was subjected to
low pressure column chromatography over silica gel 230-400 mesh
eluting with 20% ethyl acetate in hexane. The title compound was
obtained as a foam, 0.366 gram (63%), M+H=531.
Example 31
[0224] This example illustrates a process for producing
10-Benzyl-2-methyl-4-piperidin-4-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one
hydrochloride. ##STR77##
[0225] A mixture of 0.235 gram (0.44 mmole)
4-(10-benzyl-2-methyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4-yl-
)-3,6-dihydro-2H-pyridine-1-carboxylic benzyl ester and 75 mg 10%
palladium on carbon in 8 mL methanol was hydrogenated at 50 psi
hydrogen at 23.degree. for 72 hours. The mixture was filtered and
concentrated under reduced pressure. The residue was subjected to
low pressure column chromatography over silica gel 230-400 mesh
eluting with 5% methanol in chloroform containing 0.25%
concentrated ammonium hydroxide. The title compound was obtained
and converted to the hydrochloride salt, as a white foam, 0.101
gram (53%), M+H=399.
Example 32
[0226] This example illustrates a process for producing
4-(11-Oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4-yl)-piperazine-1-carb-
oxylic acid benzyl ester. ##STR78##
[0227] To 0.67 gram
4-piperazin-1-yl-10H-dibenzo[b,f][1,4]oxazepin-11-one hydrochloride
and 2.0 grams (14.5 mmole) potassium carbonate in 20 mL toluene and
10 mL water was added 0.3 mL benzyl chloroformate. To this mixture
was added 3.0 mL 4M sodium hydroxide and 5 mL THF. The reaction
mixture was stirred at 230 for 2 hours. The reaction mixture was
extracted with 30 mL ethyl acetate. The organic phase was washed
with 10 mL saturated sodium chloride, dried (magnesium sulfate) and
concentrated under reduced pressure. The title compound was
obtained as a crystalline solid from ether/hexane, 0.597 gram
(70%), m.p. 212-2130, M+H=430.
Example 33
[0228] This example illustrates a process for producing
3-[4-(4-Benzyloxycarbonyl-piperazin-1-yl)-11-oxo-11H-dibenzo
[b,f][1,4]oxazepin-10-ylmethyl]-indole-1-carboxylic acid tert-butyl
ester. ##STR79##
[0229] A mixture of 0.4 gram (0.93 mmole)
4-(11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4-yl)-piperazine-1-carb-
oxylic acid benzyl ester and 0.414 gram (3.0 mmole) powdered
potassium carbonate in 3.0 mL DMF was stirred at 230 for 5 minutes.
To this was added 0.29 g (0.93 mmole)
3-bromomethyl-indole-1-carboxylic acid tert-butyl ester (prepared
following T. K. Venkatachalam, et al, OPPI Briefs Vol. 25, No. 2,
pp. 249-251 (1993)). The reaction mixture was stirred at 230 for 16
hours. Another 0.15 g (0.48 mmole)
3-bromomethyl-indole-1-carboxylic acid tert-butyl ester was added
and the mixture was stirred for an additional 4 hours. To the
mixture was added 25 mL water. The precipitate was collected and
dissolved in 30 mL chloroform. The solution was washed with 20 mL
water, dried (magnesium sulfate) and concentrated under reduced
pressure. The residue was recrystallized from ethyl acetate/ether
to afford the title compound, 0.365 gram (60%), m.p. 205-2060,
M+H=659.
Example 34
[0230] This example illustrates a process for producing
10-(1H-Indol-3-ylmethyl)-4-piperazin-1-yl-10H-dibenzo
[b,f][1,4]oxazepin-11-one. ##STR80##
[0231] Neat
3-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-11-oxo-11H-dibenzo[b,f][1,4]oxa-
zepin-10-ylmethyl]-indole-1-carboxylic acid tert-butyl ester (0.178
gram, 0.27 mmole) was immersed in a preheated 220.degree. oil bath.
The reaction mixture was heated at 220.degree. under a nitrogen
atmosphere for 10 minutes. The glassy residue was dissolved in a
mixture of 1.0 mL ethyl acetate and 3 mL methanol. To the solution
was added a suspension of 0.1 gram 10% palladium on carbon in 3.0
mL ethanol. To this was added 5 mL THF and the mixture was
hydrogenated under 45 psi hydrogen gas at 230 for 16 hours. The
mixture was filtered and concentrated under reduced pressure. The
residue was subjected to low pressure column chromatography over
silica gel 230-400 mesh eluting with 3% methanol in chloroform
saturated with concentrated ammonium hydroxide. The title compound
was isolated as the free base, 0.050 gram (44%), m.p. 98-99.degree.
M+H=425.
Example 35
[0232] This example illustrates a process for producing
4-(4-Methyl-piperazin-1-yl)-10,11-dihydro-dibenzo[b,f][1,4]oxazepine.
##STR81##
[0233] To a solution of 0.442 gram (1.12 mmole)
tert-butyl-[4-(11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-4-yl)-piper-
azine-1-]-carboxylate in 10 mL THF was added 3.0 mL 1.0 M lithium
aluminum hydride in THF. The reaction mixture was heated under
reflux for 2 hours. Excess water was added dropwise to the mixture.
The mixture was filtered and concentrated under reduced pressure.
The residue was taken up in 5 mL 6N hydrochloric acid and washed
with two 20 mL portions of ether. The aqueous phase was cooled in
an ice bath and the pH was adjusted to 12 with 50% w/w sodium
hydroxide. The mixture was extracted with 50 mL 50% ethyl
acetate/ether. The organic phase was dried (magnesium sulfate) and
concentrated under reduced pressure. The title compound was
obtained as the solid free base, m.p. 119-1200, M+H=296.
Example 36
[0234] This example illustrates a process for producing
10-Benzenesulfonyl-4-(4-methyl-piperazin-1-yl)-10,11-dihydro-dibenzo
[b,f][1,4]oxazepine hydrochloride. ##STR82##
[0235] To a solution of 0.3 gram (1.0 mmole)
4-(4-methyl-piperazin-1-yl)-10,11-dihydro-dibenzo[b,f][1,4]oxazepine
in 2 mL THF and 4 mL chloroform was added ) 0.03 gram
dimethylpyridine-4-yl-amine, 0.15 mL triethylamine and 0.14 mL
benzenesulfonyl chloride. The reaction mixture was stirred at 230
for 72 hours. Each day, another 0.1 mL benzenesulfonyl chloride and
0.03 gram DMAP was added. The solution was concentrated under
reduced pressure. The residue was partitioned between 30 mL ethyl
acetate and 10 mL 10% sodium carbonate. The organic phase was dried
(magnesium sulfate) and concentrated under reduced pressure. The
residue was subjected to low pressure column chromatography over
silica gel 230-400 mesh eluting with 5 ethyl acetate:4.5 hexane:0.5
methanol containing 0.25% concentrated ammonium hydroxide. The
title compound was recrystallized from methanol/ethyl
acetate/ether, 0.139 gram (30%), m.p. 242-243.degree., M+H=436.
Example 37
Formulations
[0236] This example illustrates a variety of formulation
compositions.
[0237] Pharmaceutical preparations for delivery by various routes
are formulated as shown in the following Tables. "Active
ingredient" or "Active compound" as used in the Tables means one or
more of the Compounds of Formula I. TABLE-US-00002 Composition for
Oral Administration Ingredient % wt./wt. Active ingredient 20.0%
Lactose 79.5% Magnesium stearate 0.5%
[0238] The ingredients are mixed and dispensed into capsules
containing about 100 mg each; one capsule would approximate a total
daily dosage. TABLE-US-00003 Composition for Oral Administration
Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate
0.5% Crosscarmellose sodium 2.0% Lactose 76.5% PVP
(polyvinylpyrrolidine) 1.0%
[0239] The ingredients are combined and granulated using a solvent
such as methanol. The formulation is then dried and formed into
tablets (containing about 20 mg of active compound) with an
appropriate tablet machine. TABLE-US-00004 Composition for Oral
Administration Ingredient Amount Active compound 1.0 g Fumaric acid
0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben
0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg
Distilled water q.s.to 100 mL
[0240] The ingredients are mixed to form a suspension for oral
administration. TABLE-US-00005 Parenteral Formulation Ingredient %
wt./wt. Active ingredient 0.25 g Sodium Chloride qs to make
isotonic Water for injection 100 ml
[0241] The active ingredient is dissolved in a portion of the water
for injection. A sufficient quantity of sodium chloride is then
added with stirring to make the solution isotonic. The solution is
made up to weight with the remainder of the water for injection,
filtered through a 0.2 micron membrane filter and packaged under
sterile conditions. TABLE-US-00006 Suppository Formulation
Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol
1000 74.5% Polyethylene glycol 4000 24.5%
[0242] The ingredients are melted together and mixed on a steam
bath, and poured into molds containing 2.5 g total weight.
TABLE-US-00007 Topical Formulation Ingredients grams Active
compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10
Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy
anisole) 0.01 Water q.s. 100
[0243] All of the ingredients, except water, are combined and
heated to about 60.degree. C. with stirring. A sufficient quantity
of water at about 60.degree. C. is then added with vigorous
stirring to emulsify the ingredients, and water then added q.s.
about 100 g.
Nasal Spray Formulations
[0244] Several aqueous suspensions containing from about 0.025-0.5
percent active compound are prepared as nasal spray formulations.
The formulations optionally contain inactive ingredients such as,
for example, microcrystalline cellulose, sodium
carboxymethylcellulose, dextrose, and the like. Hydrochloric acid
may be added to adjust pH. The nasal spray formulations may be
delivered via a nasal spray metered pump typically delivering about
50-100 microliters of formulation per actuation. A typical dosing
schedule is 2-4 sprays every 4-12 hours.
Example 38
Radioligand Binding Studies
[0245] This example illustrates in vitro radioligand binding
studies of compound of formula I.
[0246] The binding activity of compounds of this invention in vitro
was determined as follows. Duplicate determinations of 5-HT.sub.6
ligand affinity were made by competing for binding of [.sup.3H]LSD
in cell membranes derived from HEK293 cells stably expressing
recombinant human 5-HT.sub.6 receptor. Duplicate determinations of
5-HT2A ligand affinity were made by competing for binding of
[.sup.3H]Ketanserin
(3-(2-(4-(4-fluorobenzoyl)piperidinol)ethyl)-2,4(1H,3H)-quinazolinedione)
in cell membranes derived from CHO-K1 cells stably expressing
recombinant human 5-HT.sub.2A receptor. Membranes were prepared
from HEK 293 cell lines by the method described by Monsma et al.,
Molecular Pharmacology, Vol. 43 pp. 320-327 (1993), and from
CHO-K1cell lines as described by Bonhaus et al., Br J Pharmacol.
Jun;115(4):622-8 (1995).
[0247] For estimation of affinity at the 5-HT.sub.6 receptor, all
determinations were made in assay buffer containing 50 mM Tris-HCl,
10 mM MgSO.sub.4, 0.5 mM EDTA, 1 mM ascorbic acid, pH 7.4 at
37.degree. C., in a 250 microliter reaction volume. For estimation
of affinity at the 5-HT.sub.2A receptor all determinations were
made in assay buffer containing 50 mM Tris-HCl, 5 mM ascorbic acid,
4 mM CaCl2, pH 7.4 at 32.degree. C., in a 250 microliter reaction
volume.
[0248] Assay tubes containing [.sup.3H] LSD or [.sup.3H]Ketanserin
(5 nM), competing ligand, and membrane were incubated in a shaking
water bath for 75 min. at 37.degree. C. (for 5-HT.sub.6) or 60 min.
at 32.degree. C. (for 5-HT.sub.2A), filtered onto Packard GF-B
plates (pre-soaked with 0.3% PEI) using a Packard 96 well cell
harvester and washed 3 times in ice cold 50 mM Tris-HCl. Bound
[.sup.3H]LSD or [.sup.3H]Ketanserin were determined as radioactive
counts per minute using Packard TopCount.
[0249] Displacement of [.sup.3H]LSD or [.sup.3H]Ketanserin from the
binding sites was quantified by fitting concentration-binding data
to a 4-parameter logistic equation: binding = basal + ( B .times.
.times. max - basal 1 + 10 - Hill ( log .times. [ ligand ] - log
.times. .times. IC 50 ) ##EQU1## where Hill is the Hill slope,
[ligand] is the concentration of competing radioligand and
IC.sub.50 is the concentration of radioligand producing
half-maximal specific binding of radioligand. The specific binding
window is the difference between the Bmax and the basal
parameters.
[0250] Using the procedures of this Example, compounds of Formula I
were tested and found to be selective 5-HT.sub.6 antagonists,
selective 5-HT.sub.2A antagonists, or both. For example, the
compound
8-Fluoro-4-piperazin-1-yl-10-(3-trifluoromethyl-benzyl)-10H-dibenzo[b,f][-
1,4]oxazepin-11-one exhibted a pKi of approximately 9.55 for
5-HT.sub.6, and 6-Fluoro-10-phenethyl-4-piperazin-1-yl-10H-dibenzo
[b,f][1,4]oxazepin-11-one, hydrochloride showed a pKi of
approximately 8.88 for 5-HT.sub.2A.
Example 39
Cognition Enhancement
[0251] The cognition-enhancing properties of compounds of the
invention may be in a model of animal cognition: the object
recognition task model. 4-month-old male Wistar rats (Charles
River, The Netherlands) were used. Compounds were prepared daily
and dissolved in physiological saline and tested at three doses.
Administration was always given i.p. (injection volume 1 ml/kg) 60
minutes before T1. Scopolamine hydrobromide was injected 30 minutes
after compound injection. Two equal testing groups were made of 24
rats and were tested by two experimenters. The testing order of
doses was determined randomly. The experiments were performed using
a double blind protocol. All rats were treated once with each dose
condition. The object recognition test was performed as described
by Ennaceur et al., "A new one-trial test for neurobiological
studies of memory in rats. 1: Behavioral data," Behav. Brain Res.,
1988, 31, 47-59.
[0252] While the present invention has been described with
reference to the specific embodiments thereof, it should be
understood by those skilled in the art that various changes may be
made and equivalents may be substituted without departing from the
true spirit and scope of the invention. In addition, many
modifications may be made to adapt a particular situation,
material, composition of matter, process, process step or steps, to
the objective spirit and scope of the present invention. All such
modifications are intended to be within the scope of the claims
appended hereto.
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